TP-3654 Showcases Early Signs of Tolerability, Clinical Activity in Myelofibrosis

Firas El Chaer, MD

The PIM1 kinase inhibitor TP-3654 was well tolerated and showcased preliminary signs of activity, including spleen volume reduction (SVR), symptom improvement, and broad cytokine reduction, in patients with myelofibrosis who were previously treated with or were ineligible for a JAK inhibitor, according to results from the dose-escalation portion of a phase 1/2 trial (NCT04176198).

Data presented at the 2022 ASH Annual Meeting showed that among 8 evaluable patients who were on treatment for at least 12 weeks, 6 experienced SVR. The median SVR was 11%; 5 patients had a SVR of at least 10% and 2 had a SVR of at least 35%. Additionally, 7 of the 8 patients experienced an improvement in total symptom score (TSS). The median TSS improvement was 66%, and 5 patients experienced a TSS improvement of at least 50%.

“Dose escalation is ongoing and TP-3654 appears to be well tolerated, [with] no dose-limiting toxicities [DLTs] to date,” said Firas El Chaer, MD, the lead study author and an assistant professor of medicine in the Department of Hematology/Oncology at University of Virginia Health System in Charlottesville, Virginia, in a presentation of the data. “The most common adverse effects are grade 1 gastrointestinal toxicities that resolved in 1 to 2 weeks.”

PIM1 is a proto-oncogene regulated in part through the JAK/STAT pathway, and PIM1 kinase plays a vital role in cytokine-induced signal transduction by controlling transcription factors. The upregulation of PIM1 kinase results in increased cytokines relevant to immune activation and fibrosis. In bone marrow and peripheral blood mononuclear cell samples collected from patients with myelofibrosis, a significant increase of PIM1 expression has been observed. Investigators have hypothesized that novel therapies that selectively inhibit PIM1 may provide disease-modifying effects and avoid instances of cytopenia.

“In an aggressive murine MLP myelofibrosis mouse model, PIM1 inhibition led to reduced bone marrow fibrosis, [reduced] splenomegaly, and increased [overall] survival [OS],” El Chaer added.

The phase 1/2 trial is evaluating the TP-3654 in patients with primary, post–polycythemia vera (PV), or post–essential thrombocythemia (ET) myelofibrosis who are relapsed, refractory, intolerant, or ineligible to receive treatment with JAK inhibitors.

To participate on the trial, patients are required to have a Dynamic International Prognostic Scoring System (DIPSS) score of intermediate-1, intermediate-2, or high risk; a platelet count of at least 25 x 109 cells/L; an ECOG performance status of 0 to 2; splenomegaly with a volume of at least 450 cm3; and at least 2 symptoms per the Myelofibrosis Symptom Assessment Form v. 4.0.

Thus far in the dose-escalation portion of the trial, patients were treated with single-agent TP-3654 across 5 dose levels, including 480 mg per day, 720 mg per day, 360 mg twice per day, 480 mg twice per day, and 720 mg twice per day. Dose escalation is ongoing, and investigators plan to examine doses up to 1440 mg twice per day. The trial will then determine the maximum tolerated dose (MTD) and the recommended phase 2 dose of the agent before advancing to dose expansion in phase 2.

The primary end points of the trial are safety and tolerability. Secondary end points consist of SVR, TSS reduction, OS, bone marrow fibrosis change, and pharmacokinetics.

Among 9 patients enrolled in the dose-escalation portion of the research, the median age was 71 years (range, 61-77). The median spleen length was 12 cm (range, 0-25), the median spleen volume was 2231 cm3 (range, 857-4407), and the median TSS was 18 (range, 4-62). Additionally, the median platelet count was 120 x 109cells/L (range, 68-237), and 6 patients had a platelet count of at least 100 x 109 cells/L. The median hemoglobin was 10.1 g/dL (range, 5.9-13.7), and 5 patients had a hemoglobin level of at least 10 g/dL. Notably, 2 patients were transfusion dependent.

Patients enrolled to the trial had the following myelofibrosis subtypes: primary (n = 4), post-PV (n = 4), and post-ET (n = 1). They had a DIPSS score of intermediate-1 (n = 3), intermediate-2 (n = 4), or high risk (n = 2). Additionally, 7 patients had tumors that harbored JAK2 V617F mutations, and 2 patients had a CALR mutation.

All 9 patients received prior treatment with ruxolitinib (Jakafi) for a median of 33 weeks (range, 10-268), and 2 patients received prior fedratinib (Inrebic) for a median of 36 weeks (range, 36-49). Three patients were primary refractory to JAK inhibitors, 4 experienced a loss of response, and 2 were intolerant to these agents.

As of the data cutoff date of October 11, 2022, 4 patients were still receiving treatment; this included 2 patients who received TP-3654 at 480 mg twice daily, 1 patient who was given the agent at 720 mg once daily, and 1 patient who received the drug at 720 mg twice daily. Reasons for discontinuation included physician withdrawal (n = 2), disease progression (n = 2), and patient withdrawal (n = 1). Notably, no patients discontinued due to adverse effects (AEs).

Additional data showed that cytokine reduction was observed as early as week 4 for the initial dose cohorts, and this reduction correlated with TSS reduction. Cytokines associated with myelofibrosis—including IL-6, IL-10, IL-12, IL-18, TGF-b, EGFR, ferritin, GRO-a, IL-1RA, MMP-9, PAI-1, RANTES, TIMP-1, TNFR-2, and VCAM-1—showed reduction after treatment.

Regarding safety, no DLTs or serious treatment-related AEs were reported. The most common treatment-emergent AEs (TEAEs) that were grade 1 or 2 included diarrhea (n = 7), nausea (n = 5), vomiting (n = 4), abdominal distention (n = 2), urinary tract infection (n = 2), muscle spasms (n = 2), insomnia (n = 2), fatigue (n = 2), dyspnea (n = 2), abdominal pain (n = 1), and increased bilirubin (n = 1). Grade 3 vomiting, abdominal pain, and increased bilirubin were experienced by 1 patient each.

Grade 1/2 hematological TEAEs included a decreased platelet count (n = 2), anemia (n = 1), and leukocytosis (n = 1). Grade 3 decreased platelet count, anemia, and leukocytosis were observed in 1 patient each. No patients required a dose reduction or discontinued treatment due to AEs.

“Enrollment continues as [TP-3654] monotherapy to identify the MTD, and [data] support the development of TP-3654 in combination with JAK inhibitors,” El Chaer concluded.

Reference

El Chaer F, McCloskey J, Rein LAM, et al. Preliminary data from the phase I/II study of TP-3654, a selective oral PIM1 kinase inhibitor, in patients with myelofibrosis previously treated with or ineligible for AK inhibitor therapy. Blood. 2022;140(suppl 1):594-595. doi:10.1182/blood-2022-159086